Functional Foods in Health and Disease: 4:135-160 Page 135 of 160 Review Open Access Lipid Replacement Therapy: a Functional Food Approach with New Formulations for Reducing Cellular Oxidative Damage, Cancer-Associated Fatigue and the Adverse Effects of Cancer Therapy Garth L. Nicolson 1 and Robert Settineri 2 1 Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach, CA 92647 USA 2 Sierra Research, Irvine, CA, 92606 USA Corresponding Author: Prof. Garth L. Nicolson, Department of Molecular Pathology, Institute for Molecular Medicine, P. O. Box 9355, S. Laguna Beach, CA 92652 Submission date: February 26, 2011; Acceptance date: April 21, 2011; Publication date: April 21, 2011 Abstract Background: Cancer-associated fatigue and the chronic adverse effects of cancer therapy can be reduced by Lipid Replacement Therapy (LRT) using membrane phospholipid mixtures given as food supplements. Methods: This is a review of the published literature on LRT and its uses. Results: LRT significantly reduced fatigue in cancer patients as well as patients suffering from chronic fatiguing illnesses and other medical conditions. It also reduced the adverse effects of chemotherapy, resulting in improvements in incidence of fatigue, nausea, diarrhea, impaired taste, constipation, insomnia and other quality of life indicators. In other diseases, such as chronic fatigue syndrome, fibromyalgia syndrome and other chronic fatiguing illnesses, LRT reduced fatigue by 35.5-43.1% in different clinical trials and increased mitochondrial function. Conclusions: LRT formulations appear to be useful as non-toxic dietary supplements for direct use or placed in functional foods to reduce fatigue and restore mitochondrial and other cellular membrane functions. Formulations of LRT phospholipids are suitable for addition to various food products for the treatment of a variety of chronic illnesses as well as their application in anti-aging and other health supplements and products.
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Functional Foods in Health and Disease: 4:135-160 Page 135 of 160
Review Open Access
Lipid Replacement Therapy: a Functional Food Approach with New
Formulations for Reducing Cellular Oxidative Damage, Cancer-Associated
Fatigue and the Adverse Effects of Cancer Therapy
Garth L. Nicolson1 and Robert Settineri
2
1Department of Molecular Pathology, The Institute for Molecular Medicine, Huntington Beach,
CA 92647 USA 2Sierra Research, Irvine, CA, 92606 USA
Corresponding Author: Prof. Garth L. Nicolson, Department of Molecular Pathology, Institute
for Molecular Medicine, P. O. Box 9355, S. Laguna Beach, CA 92652
Submission date: February 26, 2011; Acceptance date: April 21, 2011; Publication date: April
21, 2011
Abstract
Background:
Cancer-associated fatigue and the chronic adverse effects of cancer therapy can be reduced by
Lipid Replacement Therapy (LRT) using membrane phospholipid mixtures given as food
supplements.
Methods:
This is a review of the published literature on LRT and its uses.
Results: LRT significantly reduced fatigue in cancer patients as well as patients suffering from
chronic fatiguing illnesses and other medical conditions. It also reduced the adverse effects of
chemotherapy, resulting in improvements in incidence of fatigue, nausea, diarrhea, impaired
taste, constipation, insomnia and other quality of life indicators. In other diseases, such as
chronic fatigue syndrome, fibromyalgia syndrome and other chronic fatiguing illnesses, LRT
reduced fatigue by 35.5-43.1% in different clinical trials and increased mitochondrial function.
Conclusions: LRT formulations appear to be useful as non-toxic dietary supplements for direct
use or placed in functional foods to reduce fatigue and restore mitochondrial and other cellular
membrane functions. Formulations of LRT phospholipids are suitable for addition to various
food products for the treatment of a variety of chronic illnesses as well as their application in
anti-aging and other health supplements and products.
Functional Foods in Health and Disease: 4:135-160 Page 136 of 160
Keywords: nutritional supplements, NT factor®, Coenzyme Q10, cancer fatigue, mitochondria,
Background
Nutritional supplements are often taken to maintain health and prevent disease, but cancer
patients routinely take multiple dietary supplements to prevent recurrence of cancer, reduce the
adverse effects of cancer therapy and to improve quality of life [1-4]. Indeed, one of the most
common changes in behavior among cancer patients is initiation of the use of multiple dietary
supplements [3].
Studies conducted on the routine use of dietary supplements by cancer patients as well as
cancer survivors indicate that there is often little consideration as to their safety, efficacy and
potential negative effects [5, 6]. In fact, some data suggest that higher than recommended doses
of some vitamins and minerals might result in enhancement of carcinogenesis, changes in
survival in some cancers and interference with therapy or prescription medications [5, 6]. In
cancer patients several potentially beneficial effects of dietary supplements have been
documented, including reductions in the risk of cancer carcinogenesis and tumor progression,
enhancement of immune responses against cancer or immune systems in general, improvements
in nutrition and general health, and reductions in the adverse effects of cancer therapy [3-5, 7-
14]. Here we will focus on one of the most troublesome aspects of cancer and its therapy:
cancer-associated fatigue.
Introduction
One of the most common symptoms in cancer that can add considerably to cancer morbidity is
cancer-associated fatigue [13-16]. It exists in all types of cancers from the least to the most
progressed cancers [15, 16]. Along with pain and nausea, it is one of the most common and
troublesome symptoms of cancer [16, 17]. Cancer-associated fatigue is especially apparent in
advanced cancers where the systemic adverse effects of cancer therapy are almost always present
[17-19].
In advanced cancer patients receiving adjuvant therapies the prevalence of cancer-
associated fatigue is reported to be as high as 95% [20]. Thus cancer-associated fatigue is a
problem before, during and after therapy, and it can continue to be a problem years after cancer
treatment has stopped [16, 19]. Cancer-associated fatigue has a very strong negative effect on
quality of life; therefore, addressing and reducing cancer-associated fatigue should be an
important consideration in the treatment of cancer [14, 19].
Although not well understood, cancer-associated fatigue is thought to be a combination
of the effects of having cancer plus the effects of cancer treatments [16, 19]. Unfortunately,
cancer-associated fatigue is rarely treated, and is often thought to be an unavoidable symptom
[15, 16]. Cancer-associated fatigue can be considered to be the product of a variety of
contributing factors [21]. In addition to a decrease in the availability of cellular energy, such as
Functional Foods in Health and Disease: 4:135-160 Page 137 of 160
provided by mitochondria, there exist psychological and medical factors that determine states of
fatigue. The psychological factors include depression, anxiety, sleep disturbances, among others,
and the medical factors include anemia, endocrine changes, poor nutritional status and release of
inflammatory cytokines [11-14, 19-23]. All of these factors can all contribute to cancer-
associated fatigue [12-14].
Cancer-associated fatigue does not occur as an isolated symptom. Cancer patients
usually have a variety of symptoms, including cancer-associated fatigue. Cancer-associated
fatigue occurs as one of multiple symptoms that are present at all stages of cancer, with
exception of the very earliest stages. Cancer-associated fatigue is similar to many other
symptoms in cancer patients, in that the severity of cancer-associated fatigue usually correlates
with decreased functional abilities [24].
Cancer therapy also contributes in an important way to cancer-associated fatigue [19-21].
In fact, the most commonly found and disabling effect of cancer therapy is fatigue [20, 24, 25].
During cancer therapy fatigue problems can vary, from mild to severe, and excess fatigue during
cancer therapy is an important reason given by patients when they discontinue therapy [26].
When Manzullo and Escalante [23] reviewed the literature on the effects of cancer therapy on
cancer-associated fatigue, they found that 80-96% of patients receiving chemotherapy and 60-
93% receiving radiotherapy experienced moderate to severe fatigue. Fatigue not only was a
significant problem during cancer therapy, but it continued for months to years after the therapy
ended [23]. Thus in cancer patients suppressing cancer-associated fatigue as well as controlling
therapy-induced fatigue are important in supportive cancer care [27].
Recent research on cancer-associated fatigue has been directed at understanding and
treating cancer-associated fatigue as well as developing ways to distinguish between depression
and cancer-associated fatigue [15]. Depression is a common complaint of cancer patients. Both
cancer-associated fatigue and depression have multidimensional and heterogeneous qualities.
For example, they both possess physical, cognitive and emotional dimensions, and there is a
certain degree of overlap across these dimensions [15, 20].
Fatigue or loss of energy is a core symptom in diagnosing depression. Thus both fatigue
and depression are often diagnosed together. This is usually accomplished by self-assessment,
where fatigue and depression are considered to be part of a clinical symptom cluster, co-
morbidity or syndrome [28, 29]. There are procedures, however, that can distinguish between
cancer-associated fatigue and depression by removal of fatigue-associated assessments from an
analysis of depression [30, 31]. Criteria have been established when assessing fatigue or cancer-
associated fatigue that take depression into consideration, and these two symptoms can thus be
separated from one another by considering unshared properties [32].
Chronic fatigue lasting more than 6 months that is not reversed by normal sleep is the
most common complaint of patients seeking general medical care [33, 34]. Fatigue occurs
naturally during aging, and it is also an important secondary condition in many clinical diagnoses
[34, 35]. Most patients understand fatigue as a loss of energy and inability to perform even
Functional Foods in Health and Disease: 4:135-160 Page 138 of 160
simple tasks without exertion. Many medical conditions are associated with fatigue, including
respiratory, coronary, musculoskeletal, and bowel conditions as well as infections [33-35].
Fatigue is the most common complaint made by the overwhelming majority of cancer patients
[16, 19-21].
Fatigue and its Relationship to Oxidative Stress and Damage to Mitochondria
An important phenomenon associated with cancer and its progression as well as aging and age-
related degenerative diseases is oxidative stress [36-39]. Oxidative stress is caused by an
intracellular excess of reactive oxygen (ROS) and nitrogen (RNS) free radical species over
intracellular antioxidants. When this imbalance occurs, it results in oxidation of cellular
structures, such as membrane lipids and proteins; it also causes mutation of mitochondrial and
nuclear DNA [39-42]. The free radicals ROS and RNS are naturally occurring cellular oxidants
that are usually present in low concentrations; they are important cellular regulators and are
involved in gene expression, intracellular signaling, cell proliferation, antimicrobial defense and
other normal cellular processes [43-45]. However, when ROS/RNS are in excess over cellular
antioxidants, oxidative damage can occur to cellular structures [39, 44-46]. Recently Maes [47]
proposed a link between excess oxidative stress and activation of ROS/RNS pathways, which is
in turn linked to fatigue and fatiguing illnesses.
Cellular antioxidant defenses usually maintain ROS/RNS at appropriate concentrations
that prevent excess oxidation of cellular structures [48-50]. Some of the endogenous cellular
antioxidant defenses are mediated by glutathione peroxidase, catalase and superoxide dismutase,
among other enzymes [51, 52]. There are also low molecular weight dietary antioxidants that
can affect anti-oxidant status [53, 54]. Some of these dietary antioxidants have been used as
natural chemopreventive agents to shift the excess concentrations of oxidative molecules down
to more physiological levels [55, 56].
Excess oxidative stress and its mediators (ROS/RNS) within cancer cells have been
linked to promotion and progression of cancer malignancy (metastasis) [57-61]. To demonstrate
this oxidative stress and antioxidant status have been examined in various malignant cancers,
such as breast [58-62], prostate [63, 64], colorectal [65, 66], renal [67, 68], and other cancers
[69-71]. In all of these different cancers ROS/RNS were in excess of cellular antioxidant
concentrations, resulting in excess oxidative stress. Therefore, these cancers could have been
induced as a consequence of excess ROS/RNS and oxidative damage to the genetic apparatus
[37, 39, 72]. Even more likely than carcinogenesis is the progression of tumors that might not
evolve to malignancy in the absence of excess oxidative stress [11-14].
Excess Oxidative Stress and Severe Fatigue Caused by Cancer Therapy
Cancer therapy, such as chemotherapy, can result in the generation of excess ROS/RNS
[reviewed in 8, 9, 11, 12]. Thus cancer therapy and the resulting production of excess oxidative
stress can damage biological systems other than tumors [8, 9, 11, 12]. During chemotherapy the
Functional Foods in Health and Disease: 4:135-160 Page 139 of 160
highest known levels of oxidative stress are generated by anthracycline antibiotics, followed in
no particular order by alkylating agents, platinum-coordination complexes, epipodophyllotoxins,
and camptothecins [8, 9]. The primary site of ROS/RNS generation during cancer chemotherapy
is the cytochrome P450 monooxygenase system within liver microsomes. Enzyme systems, such
as the xanthine-xanthine oxidase system, and non-enzymatic mechanisms (Fenton and Haber-
Weiss reactions) also play a role in creating excess oxidative stress during chemotherapy [8, 9].
The very high levels of oxidative stress caused by anthracyclines is also related to their ability to
displace coenzyme Q10 (CoQ10) from the electron transport system of cardiac mitochondria,
resulting in diversion of electrons directly to molecular oxygen with the formation of superoxide
radicals [reviewed in 8, 9].
Anthracyclines and other chemotherapeutic agents cause generation of high levels of
ROS/RNS, but not all chemotherapeutic agents generate excess oxidative stress. Some agents
generate only modest amounts of ROS/RNS. Examples of this are: platinum-coordination
complexes and camptothecins, taxanes, vinca alkaloids, anti-metabolites, such as the anti-folates,
and nucleoside and nucleotide analogues [8, 9, 11, 12]. However, most chemotherapeutic agents
generate some oxidative stress, as do all anti-neoplastic agents when they induce apoptosis in
cancer cells [8, 9]. Drug-induced apoptosis is usually triggered by the release of cytochrome c
from the mitochondrial electron transport chain. When this occurs, electrons are diverted from
NADH dehydrogenase and reduced CoQ10 to oxygen, resulting in the formation of superoxide
radicals [8, 9, 73].
Chemotherapeutic agents used to treat cancer cause oxidative stress, which produces side
effects, and among the most common side effects is chronic fatigue [8, 9, 11, 12]. Chronic
fatigue caused by cancer therapy can reduce therapeutic efficacy [12, 13]. Although many anti-
neoplastic agents have clearly established mechanisms of action that are not dependent upon the
generation of ROS/RNS, these drugs can only mediate their anticancer effects on cancer cells
that are exhibiting unrestricted progression through the cell cycle. They must also have intact
apoptotic pathways. Thus oxidative stress interferes with cell cycle progression by inhibiting the
transition of cells from the G0 to G1 phase, slowing progression through S phase by inhibition of
DNA synthesis. This results in inhibition of cell cycle progression of the G1 to S phase, and it
also results in inhibition by checkpoint arrest [74-78].
Chemotherapeutic agents can also activate DNA repair systems. DNA repair of damage
caused by alkylating agents and platinum complexes results in resistance to these drugs, and
checkpoint arrest during oxidative stress can enhance the repair processes and diminish the
efficacy of treatment [79-81]. Abolishing checkpoint arrest produces the opposite effect and
enhances the cytotoxicity of anti-neoplastic agents. By reducing oxidative stress, antioxidants
counteract the effects of chemotherapy-induced oxidative stress on the cell cycle and enhance the
cytotoxicity of antineoplastic agents [8, 9].
Important intracellular signal transduction pathways that are necessary for the action of
some antineoplastic agents can also be affected by oxidative stress [8, 9, 82, 83]. There are two
Functional Foods in Health and Disease: 4:135-160 Page 140 of 160
major pathways of drug-induced apoptosis following cellular damage by anti-neoplastic agents:
(1) The mitochondrial pathway, initiated by release of cytochrome c; and (2) the CD95 death
receptor pathway, initiated by CD95L binding to its death receptor [8, 9, 81]. Oxidative stress
during chemotherapy results in the generation of highly electrophilic aldehydes that have the
ability to bind to the nucleophilic active sites of caspases as well as the extracellular domain of
the CD95 death receptor. This inhibits caspase activity and the binding of CD96L ligand,
resulting in impairment of the ability of anti-neoplastic agents to initiate apoptosis [82-84].
Similar to chemotherapy, radiotherapy also results in generation of oxidative stress and
excess ROS/RNS [85, 86]. The principal target of radiation in cancer cells is DNA, and DNA
can be directly damaged by radiation. However, genetic damage is also mediated by excess
ROS/RNS [86, 87]. Recently the principal source of excess ROS/RNS during radiotherapy has
been shown to be mitochondrial [87, 88]. Thus the initial cytotoxicity of radiation is now
thought to be due to excess ROS/RNS, which triggers apoptosis via alteration of mitochondrial
metabolism. This causes transiently opening of mitochondrial permeability transition pores,
which increases the influx of calcium ions into the mitochondrial matrix. The influx of calcium
ions stimulates mitochondrial nitric oxide synthase and generation of nitric oxide, which then
inhibits the respiratory chain and eventually stimulates excess ROS/RNS free radicals that
initiate apoptosis [88, 89].
Cancer Therapy, its Adverse Side Effects and Damage to Cellular Mitochondria
Cancer therapy is associated with several adverse side effects. One of the most difficult side
effects is caused by chemotherapeutic drug (or radiotherapeutic) damage to mitochondria [8, 9,
11, 12]. Cardiac mitochondria are especially sensitive to certain chemotherapy agents, such as
anthracycline antibiotics [8, 9]. Anthracycline-induced cardiac toxicity is characterized by acute,
reversible toxicity that causes electrocardiographic changes and depressed myocardial
contractility and by chronic, irreversible, dose-related cardiomyopathy [9, 90]. The selective
anthracycline-induced toxicity to cardiac cells is due to damage to cardiac mitochondria. The
sensitivity of cardiac cells to anthracyclines, such as doxorubicin, has been found to be due to the
unique properties of cardiac mitochondria, which possess a Complex I-associated NADH
dehydrogenase in the inner mitochondrial membrane facing the mitochondrial cytosol [91, 92].
Small molecules can penetrate the outer mitochondrial membrane; thus doxorubicin as a
relatively small molecule can readily penetrate the outer mitochondrial membrane [90, 93].
However, because it is hydrophilic and cannot partition into the lipid membrane matrix, it cannot
penetrate the inner mitochondrial membrane [93]. Thus, it cannot participate in oxidation-
reduction reactions with the type of inner matrix-facing, electron transport chain dehydrogenases
found in most types of cells, including most tumor cells [90, 93]. But in heart cells doxorubicin
can interact with the mitochondrial cytosolic-facing NADH dehydrogenase that is unique to this
tissue [94, 95]. This interaction produces doxorubicin aglycones, which are highly lipid soluble
Functional Foods in Health and Disease: 4:135-160 Page 141 of 160
and readily penetrate the inner mitochondrial membrane [90, 93]. At this location they can
displace CoQ10 from the electron transport chain [90, 94].
The displacement of CoQ10 from the electron transport chain during doxorubicin
treatment results in decreased CoQ10 in cardiac muscle [96]. This occurs as the plasma
concentration of CoQ10 increases [97]. CoQ10 normally accepts electrons from Complexes I and
II and transfers them down the electron transport chain, resulting in the formation of water.
However, the presence of aglycones in the inner mitochondrial membrane and inner matrix
results in the transfer the electrons directly to molecular oxygen, resulting in the formation of
superoxide radicals [98]. Thus, doxorubicin generates a high level of oxidative stress in cardiac
mitochondria, causing acute cardiac toxicity and damage to mitochondrial DNA [90, 95, 99].
Cardiac cells that are damaged by anthracyclines cannot sustain their function, and
changes in their structure, mostly disruption of mitochondria, eventually results in apoptosis [90,
100]. This produces cardiac insufficiency and an inability to respond to pharmacological
interventions, resulting ultimately in cardiac failure. However, if CoQ10 is administered during
anthracycline chemotherapy, damage to the heart is prevented by decreases in anthracycline
metabolism within cardiac mitochondria and by competing with aglycones for the CoQ10 sites
within the electron transport chain [8, 9, 90]. Thus, CoQ10 administered concurrently with
anthracyclines can maintain the integrity of cardiac mitochondria and prevent damage to the
heart, and at the same time enhancing the anti-cancer activity of anthracyclines [8, 9, 90].
In addition to chemotherapy, radiotherapy also produces damage to tissues other than
cancer tissues. Agents that protect tissues against radiation effects have been used to reduce
unwanted damage [88, 101]. Such radioprotective agents that have been used to decrease the
adverse effects of radiotherapy are: antioxidants, free radical scavengers, inhibitors of nitric
oxide synthase and anti-inflammatory and immunomodulatory agents [88, 101]. The most
effective of these target mitochondria, such as proteins and peptides that can be transported into
mitochondria and plasmids or nucleotide sequences. For example, agents that target and
stimulate mitochondrial manganese superoxide dismutase genes can be used as radioprotective
agents [88].
Molecular Replacement of Mitochondrial Components During Cancer Therapy
Replacement of CoQ10 during chemotherapy dramatically prevents development of
anthracycline-induced cardiomyopathy and histopathological changes in heart tissue [9, 90].
Administering CoQ10 can also prevent changes in electrocardiograms (EKG) characteristic of
anthracycline-induced heart damage [102]. In animals the administration of CoQ10 resulted in
increased survival, improvement in their EKG patterns, and reduced heart histopathological
changes [103]. These preclinical data, along with clinical data [discussed in 11, 12, 90] support
the contention that CoQ10 protects the heart tissue from anthracycline-induced damage.
During chemotherapy with anthracyclines in some institutions cancer patients have
received concurrent administration of CoQ10 to prevent both chronic and acute cardiotoxicity [9,
Functional Foods in Health and Disease: 4:135-160 Page 142 of 160
11, 12, 90]. For example, the importance of administering CoQ10 on the development of
doxorubicin-induced cardiotoxicity in patients with lung cancer has been studied by Judy et al.
[104]. Doxorubicin given alone without CoQ10 caused marked impairment of cardiac function
with a significant increase in heart rate and a substantial decrease in ejection fraction, stroke
index and cardiac index. In contrast, doxorubicin administered along with CoQ10, did not cause
cardiotoxicity, and cardiac function remained unchanged [104]. Other studies have confirmed
these results and have shown that CoQ10 can reduce the cardiac toxicity of doxorubicin in adults
[105, 106] and also in children [107, 108]. Thus in preclinical and clinical studies the data
indicate that CoQ10 protects the heart from the cardiotoxicity of anthracyclines.
Cancer-Associated Fatigue and Other Adverse Effects of Therapy
The most common complaint of patients undergoing anti-neoplastic therapy is fatigue, but there
are also other complaints of patients that are undergoing cancer therapy [13, 14]. These include:
pain, nausea, vomiting, malaise, diarrhea, headaches, rashes and infections [23, 106, 108]. Other
more serious problems can also occur, such as cardiomyopathy, peripheral neuropathy,
hepatotoxicity, pulmonary fibrosis, mucositis and other effects caused by therapy [23, 26, 106,
108]. In terms of their cancer-associated fatigue, most patients feel that cancer therapy-caused
fatigue is an untreatable symptom [25]. Although fatigue is usually the most commonly reported
adverse symptom during cancer therapy, up until recently there was little effort directed at
reducing fatigue before, during or after cancer therapy [109]. The perception that cancer-
associated fatigue is an untreatable symptom has changed recently [12, 14].
Reducing cancer-associated fatigue and fatigue associated with cancer therapy are now
considered important therapeutic goals. Psychological, physical, pharmaceutical and
nutraceutical methods have been undertaken to reduce fatigue and improve the quality of life of
cancer patients [14, 23, 111]. Such treatments are based mainly on suppressing fatigue but also
on controlling co-morbid or related symptoms, such as pain, anemia, cachexia, sleep disorders,
depression and other symptoms [14, 23, 111-115].
Unfortunately, there is no standard protocol related to treating cancer-associated fatigue
and related symptoms. In reviewing the types of supportive measures used to control fatigue and
related symptoms, the data suggest that graded exercise, nutritional support, treatment of
psychological problems (such as depression with certain anti-depressants or psycostimulants),
treatment of anemia with hematopoetic growth factors and control of insomnia with cognitive
behavioral therapy or pharmacological and nonpharmacological therapies all have a role to
various degrees in controlling cancer-associated fatigue [110-115]. Some of these approaches,
such as the use of pharmacological drugs and growth factors, have been systematically meta-
analyzed in 27 studies [116]. In this limited analysis, only a psycostimulant (methylphenidate)
and hematopoetic growth factors (erythropoietin and darbopeitin) were more effective than
placebo treatments. Other treatments were no better than placebo in the treatment of cancer-
related fatigue 116].
Functional Foods in Health and Disease: 4:135-160 Page 143 of 160
Cancer-Associated Fatigue, Aging and Mitochondrial Membrane Damage
As discussed above, cancer-associated fatigue has been defined as a multidimensional sensation
[14, 35, 112, 113, 116]. Most patients understand fatigue as a loss of energy and inability to
perform even simple tasks without exertion [116, 117]. Cancer-associated fatigue has been
described as the dysregulation of several interrelated physiological, biochemical and
psychological systems [112, 113], but at the tissue and cellular levels fatigue is related to
reductions in the efficiency of cellular energy systems, mainly found in mitochondria [13, 14,
118]. Damage to mitochondrial components, mainly by ROS/RNS oxidation of membrane
phospholipids, can impair mitochondrial function, and this can also result in oxidative damage to
other cellular structures [reviewed 36, 42, 44]. Mitochondrial membranes and DNA are major
targets of oxidative stress, and with aging ROS/RNS mitochondrial damage can accumulate [80,
119].
During aging and in certain medical conditions oxidative damage to mitochondrial
membranes impairs mitochondrial function [80, 119, 120]. For example, in chronic fatigue
syndrome patients evidence of oxidative damage to DNA and lipids exists [120, 121] as well as
oxidized blood markers [122] and muscle membrane lipids [123] that are indicative of excess
oxidative stress [124]. In chronic fatigue syndrome patients also have sustained elevated levels
of peroxynitrite due to excess nitric oxide, which can result in lipid peroxidation and loss of
mitochondrial function as well as changes in cytokine levels that exert a positive feedback on
nitric oxide production, increasing the rate of membrane damage [126].
Lipid Replacement Therapy of Oxidized Membrane Components and its Effect on Fatigue
In cancer patients mitochondrial membranes as well as other cellular membranes are especially
sensitive to oxidative damage by ROS/RNS, which occurs at high rates in cancer [65, 66, 68-71,
124]. Oxidation of membrane phospholipids alters their structure, affecting lipid fluidity,
permeability and membrane function [124, 126, 127]. One of the most important events caused
by ROS/RNS damage is loss of electron transport function, and this appears to be related to